Diabetes mellitus is a major public health problem affecting approximately 5-10% of the population in the United States. About 1 in 5 individuals over 65 years of age is being treated for this disorder. Early diagnosis and treatment can diminish the morbidity and early mortality associated with this disorder. Both genetic and non-genetic factors play a role in the development of diabetes mellitus. There are at least three clinically distinct syndromes of diabetes mellitus, each of which has heterogenous genetic contributions: Type 1 or insulin dependent diabetes mellitus(IDDM); Type 2 or non-insulin dependent diabetes mellitus (NIDDM) and maturity-onset diabetes of the young (MODY). Generally, through a careful analysis of the family history, personal medical history, physical examination and laboratory studies it is possible to determine which type of diabetes a patient has. Without such careful study, many patients are improperly classified, generally without significant clinical consequence. In many families, multiple diabetic syndromes co-exist and some investigators have hypothesized that the genetics of the three conditions may overlap. Furthermore there is some evidence that the complications of diabetes may have independent genetic causes. For example, diabetic nephropathy is the major determinant of premature morbidity and mortality in insulin dependent diabetes mellitus (IDDM). This complication, which affects only one third of all IDDM subjects, reaches its incidence peak between 10 and 20 years of diabetes and then declines; such a pattern would be expected only is a subgroup of IDDM patients is susceptible to renal complications. Studies which found clustering of diabetic nephropathy in families also provide support for the hypothesis that genetic factors contribute to differences in the angiotensin I-converting enzyme gene (ACE) may contribute to genetic susceptibility to diabetic nephropathy in IDDM. Thus there are tremendous gaps in our understanding of the genetics of the various diabetic syndromes. We hope to clarify some of these issues through the careful study of large number of pedigrees of families with diabetes. It is expected that through the study of the medical history and C-peptide measurements we should be able to classify patients with diabetes into one of the three categories - IDDM, NIDDM and MODY. By measuring the fasting glucose levels and the glucose response during an oral glucose tolerance test, we will be able to define the status of glucose tolerance in family members of patients with diabetes. In some patients we are likely to make new diagnoses of diabetes or impaired glucose tolerance. In others a fasting glucose of >105 mg/dl may indicate a high risk for diabetes and has been a useful cut-off for genetic studies. Body mass index (BMI), waist to hip ratio, presence of acanthosis nigricans, blood pressure, fasting insulin levels and lipid profiles as aspects of medical history may be independent marker of insulin progression to diabetes. DNA will be isolated from 20 ml of peripheral blood from an individual for para- and non-parametric linkage studies as well as association studies. The combination of numerous carefully characterized pedigrees of individuals with a family history of diabetes and DNA for further genetic and molecular studies should provide an invaluable resource for the study of diabetes and its complications.